IL-21 is a recently described cytokine that is secreted by activated CD4 T cells. It is a member of the family of cytokines for which the common gamma chain is a component of the receptors for interleukin-2 (IL-2), IL- 4, IL-7, IL-9, IL-15 and IL-21. The IL-21 R is expressed on T cells, NK, B cells, and monocyte-derived dendritic cells. Among these cytokines, IL-2, IL-7 and IL-15 have been implicated in T cell homeostasis, allowing T cells to proliferate in vivo in the absence of antigen, thereby maintaining a pool of central memory T cells (TCM) and effector memory T cells (JEM) with distinct effector function and homing capacity. Although IL-21 shares many similarities with IL-2 and IL-15, its role in modulating antigen dependent and antigen-independent memory T cell proliferation, differentiation and function are unknown. In HIV infection, a state of lymphopenia ensues, putting pressure on homeostatic mechanisms which are not well defined. Preliminary studies in HIV infected subjects in our laboratory implicate a deficiency of the common gamma chain in CD4 and CD8 T cells, and a deficiency of antigen-induced IL-2 production by CD4 T cells in HIV infected subjects. Although antigen dependent responses were deficient, antigen independent proliferation in presence of homeostatic cytokines appeared to be intact. Given the wide cellular subtypes that express IL-21 R and the secretion of IL-21 exclusively by CD4 T cells, it is highly likely that IL-21 is involved in HIV pathogenesis. This proposal aims to test the hypothesis that the novel cytokine IL-21 is an essential component of T helper cell function which may be compromised in HIV infection. Further, that exogenous IL- 21 can invigorate lethargic memory CD8 T cells to expand, survive and undergo antigen-independent differentiation into efficient effector CDS T cells. The mechanism of IL-21 activity on memory cells will be compared with IL-2 and IL-15. These studies can lay the groundwork towards development of a novel therapeutic agent for immune reconstitution and for vaccine adjuvants in HIV infected people.